Latent Autoimmune Diabetes In Adults Pdf
The term “latent autoimmune diabetes in adults” (LADA) is used more commonly than “slow.
Context: The aim of this review was to explore the pathogenic and clinical spectrum of type 1 diabetes, which includes a form of adult onset autoimmune diabetes usually referred to as latent autoimmune diabetes in adults (LADA). We looked at this entire range of forms of autoimmune diabetes as a spectrum of genetic and nongenetic environmental influences, diabetes-associated immune responses, and metabolic changes.
Evidence Acquisition: We assessed epidemiological, genetic, immunological, and clinical data from major articles on autoimmune diabetes, including LADA and type 1 diabetes, published since 1992.
Evidence Synthesis: Data analysis of autoimmune diabetes indi-cates that type 1 diabetes and LADA occupy different poles of the same spectrum.
Conclusion: Evidence is presented that LADA represents one end of a rainbow encompassing type 1 diabetes. The clinical nature and management of autoimmune diabetes poses important therapeutic questions regarding conventional therapy for hyperglycemia as well as therapy aiming to protect residual β-cell function. Limiting loss of endogenous insulin secretion using immunomodulation could be valuable, not only for LADA but also for type 1 diabetes.
TYPE 1 DIABETES RESULTS from the destruction of the insulin-secreting islet cells by an immune mediated process. This adverse immune response is induced and promoted by the interaction of genetic and environmental factors and is one of a group of autoimmune diseases that affect about 10% of the population in the developed world. Type 1 diabetes used to be defined in terms of the absolute need for insulin therapy (insulin-dependent diabetes) or, before that, the age at onset of the disease (juvenile onset diabetes). These defining features were then abandoned in favor of the term type 1 diabetes (1) when it became apparent that not everyone with autoimmune diabetes is either a juvenile or necessarily exhibits an absolute insulin requirement.
Individuals diagnosed with autoimmune diabetes, i.e. diabetes associated with diabetes-associated autoantibodies, when they are adults may not initially require insulin treatment and have been classified as having latent autoimmune diabetes of adults (LADA) (2, 3), latent because without testing for diabetes-associated autoantibodies it would not be possible to identify these patients as having autoimmune diabetes and adult because at that time it was suggested that this form of diabetes was not present in juveniles. This form of diabetes has also been called slowly progressing insulin-dependent diabetes (4) or type 1.5 diabetes (5). The aim of this article was to explore the clinical and pathogenic spectrum of autoimmune diabetes that extends into and includes LADA.
LADA is defined by three features including: adult age at diagnosis, the presence of diabetes-associated autoantibodies, and delay from diagnosis in the need for insulin therapy to manage hyperglycemia. However, the first and last are not categorical traits, being dependent on the mode of ascertainment and decision making by physicians. The second feature lacks disease specificity because it is based on positivity for autoantibodies found in type 1 diabetes mellitus. In a recent review (6), it was suggested that LADA patients should be diagnosed with non-insulin-requiring diabetes at age 30 yr or older and that age (range 30–70 yr) was also used in a major European Union initiative (http://www.actionlada.org); in addition, both defined LADA to include patients who had 6 months without insulin treatment after diagnosis (6). Other large studies of autoimmune non-insulin-requiring patients have included selected cases, cases not taking any pharmacological agent, or avoided a definition entirely (7–9). Difficulties with the performance of islet cell and insulin autoantibody assays precluded them from being used routinely in defining LADA. Because insulinoma-associated antigen (IA)-2 autoantibodies are usually found with glutamic acid decarboxylase (GAD) autoantibodies but rarely in LADA, this condition is broadly defined by the presence of GAD autoantibodies. However, GAD autoantibodies are also found in type 1 diabetes mellitus, so it follows that using them in the definition of LADA lacks disease specificity (10). The epidemiology of LADA is also influenced by geography, genetic susceptibility, environmental factors, gender, and age at diagnosis. In Northern Europe and North America, about 5–10% of newly diagnosed non-insulin-requiring diabetes patients have LADA, according to the mode of ascertainment, the sourced population, the age of the patient (frequency is higher in younger age groups), and the definition of the disease (5, 6, 10).
LADA at One End of a Spectrum of Genetic Susceptibility
The epidemiology of autoimmune diabetes including type 1 diabetes is influenced by genetic susceptibility, which modifies age at onset (6). There is evidence in autoimmune diabetes for a continuum of genetic susceptibility, which extends from a marked effect in childhood-onset type 1 diabetes to the relatively limited effect detected in LADA (Table 1). Survival analysis estimates that nondiabetic identical twins of probands diagnosed with type 1 diabetes under 25 yr of age have a 38% probability of developing diabetes, compared with only 6% for twins of probands diagnosed later (11–13) (Table 2). Such a remarkably low twin concordance for adult-onset type 1 diabetes implies that the genetic impact in adult-onset diabetes is limited (14, 15), favoring a substantial impact of environmental factors. There is an age-related continuum in diminishing twin concordance, suggesting that the decline in genetic influence is gradual, consistent with a phased influence on a single disease, type 1 diabetes, rather than an age-related step-wise effect resulting from two distinct diseases. There are, as yet, no twin studies of LADA. Of genes implicated in the genetic susceptibility to type 1 diabetes and LADA, the most important, for both, are in the histocompatibility [human leukocyte antigen (HLA)] region of chromosome 6 (14).
Genetic, immunological, and metabolic differences between childhood-onset and adult-onset type 1 diabetes and LADA
| 6 (>25) | ||
| US (Ref.12) | 44 (<15) | 13 (>15) |
| Finland (Ref.13) | 50 (<10) | 23 (>10) |
| 6 (>25) | ||
| US (Ref.12) | 44 (<15) | 13 (>15) |
| Finland (Ref.13) | 50 (<10) | 23 (>10) |
Note the substantially lower concordance rates in the older-onset twins consistent with a marked nongenetically determined effect causing diabetes in them.
Concordance for type 1 diabetes in identical twins according to age at clinical onset in the index twin
| 6 (>25) | ||
| US (Ref.12) | 44 (<15) | 13 (>15) |
| Finland (Ref.13) | 50 (<10) | 23 (>10) |
| 6 (>25) | ||
| US (Ref.12) | 44 (<15) | 13 (>15) |
| Finland (Ref.13) | 50 (<10) | 23 (>10) |
Note the substantially lower concordance rates in the older-onset twins consistent with a marked nongenetically determined effect causing diabetes in them.
HLA alleles associated with type 1 diabetes susceptibility include HLA DR3, DQB1*0201, and DR4, DQB1*0302, whereas others are associated with disease protection, e.g. HLA DR2, DQB1*0602 (16–19). Children with type 1 diabetes show an increased prevalence of the heterozygous alleles HLA DR3, DQB1*0201, and DR4, DQB1*0302, the proportion of heterozygotes declining with age at diagnosis (19). Children with the diabetes-protective HLA DR2, DQB1*0602, are unlikely to develop diabetes (20), whereas in type 1 diabetes of adult-onset and LADA, the same alleles carry less protection (21, 22) (Table 1). Nevertheless, both the latter and LADA show HLA genetic susceptibility with little or no HLA genetic protection (19–21).
Strikingly, even adults with non-insulin-requiring diabetes without the diabetes-associated autoantibody to GAD have an excess of diabetes-associated HLA alleles and are relatively young and lean (7, 23–25). Age-related genetic factors also influence the risk of type 1 diabetes. Not only is the age incidence of type 1 diabetes lower in adults than in children, the range of incidence across European countries is also reduced in adults (26). Furthermore, there is a male excess in incidence that becomes evident during puberty and is most striking in the age group 25–29 yr (26).
A recent, albeit small, genetic study (8) found similar HLA susceptibility genes in both type 1 diabetes and LADA. Other genes have been linked to type 1 diabetes and these genes, including TNFα, TNFβ, IL-10, IL-6 gene polymorphisms, and IL-18 gene promoter polymorphism, but they have yet to be studied comprehensively in LADA (27, 28). Other gene polymorphisms within the CTLA4, PTPN22, IRS-1, ICOS, and SUMO4 genes confer a substantial risk to type 1 diabetes with odds ratios between 1.8 and 2.5 but have not been studied in LADA (29).
In the light of these observations, it remains possible that LADA represents one end of a rainbow of autoimmune diabetes, which is distinguished from classic type 1 diabetes only because it is diagnosed in adulthood and presents with some clinical, anthropometric, and metabolic features more commonly associated with type 2 diabetes.
LADA in a Spectrum of Nongenetic Influences
Nongenetic factors play a major role in causing type 1 diabetes as shown by studies of populations that have migrated, populations with changing disease incidence, and twins. We know little of the current incidence of autoimmune diabetes in adults and LADA. The incidence of a range of autoimmune diseases, including diabetes, has increased notably over the last three decades (30). The current low selection density and relative stability of HLA gene polymorphisms indicates that this increasing incidence cannot be due to genetic selection pressures and is most likely the result of nongenetic factors (10, 15).
Unfortunately, population studies are of limited value in identifying the impact of nongenetic factors because it is difficult to segregate genetic from environmental influences. However, changes in disease incidence within a genetically stable population are important when disease incidence rises rapidly or changes abruptly as in migrants (31, 32). Migrant studies support a role for environmental factors influencing disease incidence (32, 33). Type 1 diabetes incidence in Asian children in families who have migrated to Britain increased from 3.1 per 100,000 per year in 1978–1981 to 11.7 per 100,000 per year in 1988–1990, much higher than in their native Karachi (1 per 100,000 per year) (29, 30). However, Sardinian migrants moving to continental Italy retained the high incidence of the ancestry region, suggesting that it is the genetic susceptibility that determines the prevalence of the disease in response to the environmental factors (34). There are no comparable migration studies of adults with type 1 diabetes or of LADA patients. On the other hand, the identical twin concordance for adult-onset type 1 diabetes is low, implying that the genetic impact on this form of diabetes is limited, which in turn suggests a major impact of environmental factors (10). The declining identical twin concordance rate for type 1 diabetes with increasing age appears to be a continuum and not a categorical phenomenon, in line with an age-related spectrum of environmental impact on the etiology of autoimmune diabetes. However, there are no twin studies in LADA, so it is unclear whether this spectrum extends into that form of autoimmune diabetes.
LADA at One End of a Spectrum of Diabetes-Associated Immune Responses
At birth, children of mothers with diabetes may have islet cell autoantibodies (ICAs), insulin autoantibodies (IAAs), and GAD autoantibodies. But these autoantibodies can also be found in the maternal serum and are probably placentally transferred to the child because autoantibody specificities are similar in mother and cord blood and are not usually detected in the infants of mothers without such autoantibodies (35–37). Passively acquired maternal autoantibodies disappear after birth as expected but can subsequently be replaced by the infant’s own autoantibodies.
Diabetes-associated autoantibodies can appear at a later stage. In one study, three of 58 infants of diabetic mothers developed IAAs, ICAs, and GAD de novo by 2 yr of age, and only then were autoantibodies associated with diabetes risk (35), and in another study,137 children with ICAs from a prospective Finnish study of 4590 consecutive newborns with the disease-risk HLA-DQB1, IAAs, and GAD autoantibodies usually appeared in childhood before ICAs, whereas IA-2 autoantibodies usually appeared later when IAAs are uncommon (38). In contrast to LADA and adult-onset type 1 diabetes, children often have IAAs at diagnosis and, in them, IAA is highly predictive of the disease (39). Because seroconversion continued up to at least age 10 yr of age, it follows that the induction event with activation of immune response to produce diabetes-associated autoantibodies is not confined to early childhood. It remains unclear whether the age at clinical diagnosis is in part dependent on the age at which an environmental event activates the immune response. If this is the case, then the immune process that leads to adult-onset type 1 diabetes and LADA would be induced later in them than in childhood-onset type 1 diabetes.
Taken together these observations suggest that activation of the diabetes-associated immune process can occur in early childhood when it is more likely to be associated with IAAs in those who progress to childhood-onset type 1 diabetes. But the induction of diabetes-associated autoantibodies is not confined to early childhood. Currently we have no clear evidence identifying the age of induction of diabetes-associated autoantibodies in those subjects who develop either adult-onset type 1 diabetes or LADA. However, we know that these diabetes-associated autoantibodies, when detected in adult life, are predictive of an ongoing β-cell destructive process.
In this respect the prevalence of autoantibodies to protein tyrosine phosphatase isoforms IA-2 and IA-2β/phogrin has been recently examined in a cohort of adult U.K. Prospective Diabetes Study patients thought to have type 2 diabetes to determine whether these autoantibodies predict a requirement for insulin therapy (37). In this cohort the presence of IA-2A was infrequent (about 2%), associated with the HLA-DR4 haplotype as is the case in classic type 1 diabetes and highly predictive of insulin therapy (positive predictive value 60%). The measurement of IA-2βA does not provide additional information (40).
LADA at One End of a Spectrum of Metabolic Changes
There is evidence in autoimmune diabetes for a continuum of metabolic changes, predominantly decreased insulin secretory capacity, but also insensitivity to insulin. These extend from the severe changes seen in childhood-onset type 1 diabetes to the relatively minor changes initially detected in LADA.
Some individuals pass through a prediabetic stage of impaired glucose tolerance or even non-insulin-requiring diabetes before becoming frankly insulin dependent (41). Diabetes Prevention Trial of Type 1 Diabetes detected 585 relatives of type 1 diabetic patients who had ICAs plus either IAAs or low first-phase insulin response to iv glucose (42). Of these, 427 had normal glucose tolerance, 87 impaired glucose tolerance, and 61 were diabetic, yet asymptomatic (39). Of the latter, those with impaired fasting glucose were significantly older (mean age 21 yr) than those with normal fasting glucose (mean age 12 yr). These subjects with asymptomatic autoimmune diabetes resemble LADA, but their age is less than 30 yr precluding the diagnosis. It follows that some patients with autoimmune diabetes pass through a phase of altered glucose levels including non-insulin-requiring diabetes before becoming insulin dependent, and the frequency of this phase, to a degree, is age dependent. It remains to be determined whether all children with diabetes-associated autoantibodies will progress to diabetes, let alone insulin-dependent diabetes. The rate of progression to clinical diabetes is more rapid in patients presenting younger than 5 yr of age than in those presenting much later (43). Histological evidence supports this contention: islet β-cells tend to be absent within 12 months of diagnosis in patients aged younger than 7 yr but detected for longer periods in older patients (44). Variability in progression to clinical diabetes can even be detected in very young children; for example, of children identified between 1 and 5 yr of age with diabetes-associated autoantibodies and subnormal insulin responses, half of them progress rapidly to diabetes, whereas the remainder are free from diabetes up to 4 yr later (45). Other studies have noted such variable progression to type 1 diabetes, which is more rapid in obese than lean children (46) and in children than adults (47–50). From these observations it follows that there is a spectrum in the rate of metabolic decompensation during the prediabetic period in autoimmune type 1 diabetes, but no data are available, as yet, in LADA.
Insulin secretory capacity is less in children than adults at the onset of type 1 diabetes and after diagnosis deteriorates more rapidly. A study of 235 consecutive cases with newly diagnosed type 1 diabetes found that those aged younger than 7 yr had the lowest baseline residual insulin secretion and required the highest insulin dose for optimal control, whereas the older the age at diagnosis, the higher was the basal C-peptide level (51). Patients with LADA also have reduced fasting and stimulated C-peptide at diagnosis, although the levels of C-peptide are higher than those found in children and similar to those found in adult-onset type 1 diabetes (8). However, after diagnosis, the C-peptide levels have been reported to fall more rapidly in childhood-onset type 1 diabetes than in adult-onset type 1 diabetes and in the latter more rapidly than in LADA (52–55). Furthermore, persistent C-peptide secretion, implying less aggressive disease, is detected in more adults than adolescents after diagnosis of type 1 diabetes and in more adolescents than prepubertal children with diabetes (52–54). Other studies report a quite rapid loss of C-peptide even in LADA, which argues against a chronic destructive process in that condition (6, 55, 56). In summary, there is a continuous spectrum of loss of insulin secretory capacity, the severity of which can be age related, being more severe in children than adults with type 1 diabetes and more severe in the latter than in LADA subjects, although some patients with LADA may show a rapid loss of insulin secretory capacity.
The metabolic decompensation that leads to frank diabetes could result from either increased linear growth, which has been linked to diabetes risk, or increased childhood obesity, which has been correlated with age at presentation (10, 46). People with LADA may well have more severe loss of insulin sensitivity than in childhood-onset type 1 diabetes, but there are only two small studies (57, 58) considering insulin sensitivity in LADA, and both used the homeostasis model of assessment, whereas no studies have used the gold standard euglycemic hyperinsulinemic clamp. Certainly in LADA the frequency of the metabolic syndrome, usually associated with insulin resistance, although less prevalent than in type 2 diabetic patients of similar age, is more prevalent than in the general population (9). In a recent report, the metabolic syndrome, which is found in approximately 22% of the North American population was identified in 74% of those with LADA but in significantly more subjects with type 2 diabetes (84%) (9).
It is likely, therefore, that within autoimmune diabetes, including both type 1 diabetes and LADA, there is an age-related spectrum of decreasing insulin secretory capacity and increasing insulin insensitivity associated with the metabolic syndrome. The distinction between LADA and adult-onset classical type 1 diabetes is a matter of debate. It is possible that the distinction between the two is one of degree, with the classical type 1 diabetes being at one end of the spectrum and LADA, when it remains insulin independent, being at the other end.
A Spectrum of Clinical Management in LADA
Type 1 diabetes progresses to insulin dependence usually within 2 yr of the clinical diagnosis as noted in the preinsulin era. Before 2 yr some patients may have a partial or complete remission when insulin therapy is not required (59). Of LADA patients, in one study (7), 94% required insulin treatment by 6 yr as compared with only 14% in those initially non-insulin-requiring diabetes patients without either GAD autoantibodies or ICAs. Progression to insulin dependence in LADA patients was more rapid in those aged younger than 45 yr than in older cases (7). It follows that patients with autoimmune diabetes, including both type 1 diabetes and LADA, are at high risk of progression to insulin dependence, but that risk declines with age at diagnosis.
It is well established that insulin is the treatment of choice for type 1 diabetes, but there is no established management strategy for patients diagnosed with LADA (60–65). The European Union, therefore, funded a major initiative (ACTION-LADA) to study the characteristics of LADA and report on how to treat it. In considering how to treat LADA, some important questions arise as to our broad management of autoimmune diabetes. Because the predominant defect in autoimmune diabetes is loss of insulin secretion, should we treat the disease with insulin irrespective of the level of dependency on insulin? Autoantibody positive, initially non-insulin-requiring, diabetic patients initially treated with sulfonylureas have been found to require insulin earlier than autoantibody-negative patients, but sulfonylureas did not have an impact on the need for insulin treatment or the time to progression to insulin therapy (41).
Metformin is routinely offered to patients with non-insulin-requiring diabetes, but its specific role in LADA is unclear, and the drug may be contraindicated in those with LADA because there is a theoretical risk of severe metabolic disturbance in individuals who progress to insulin dependency while on it. Intriguingly, however, there is limited evidence that metformin could be of value, even in patients with type 1 diabetes. For example, in one study, adolescent type 1 insulin-dependent diabetes patients given metformin subsequently showed a significantly lower hemoglobin A1c and reduced insulin requirements, compared with those not taking metformin (62).
Thiazoledinediones also might theoretically be of value because they not only improve insulin sensitivity but also have an antiinflammatory effect and protect nonobese diabetic mice, a well-established model of autoimmune diabetes, from developing diabetes (63). In a small study of LADA patients in China (64), there was a significant improvement in C-peptide but not hemoglobin A1c in patients receiving rosiglitazone plus insulin, compared with insulin alone.
Because the primary defect in autoimmune diabetes is loss of insulin secretion, treatment should aim to restore islet insulin secretion. Therapy to prevent progression toward insulin dependency could include insulin or immunomodulation, given the inflammatory nature of the disease process thought to cause insulin secretory cell destruction. The optimal insulin regimen is unclear; given the broad loss of insulin secretory capacity, it might be argued that the early introduction of a long-acting insulin could be beneficial. Alternatively, the loss of rapid insulin release in LADA patients suggests that replacement with a fast-acting insulin would be more valuable.
One study in Japan of patients with LADA compared early treatment with insulin given as multiple injections with sulfonylureas (61). Although of limited power, this study did show a statistically significant persistence of C-peptide in the insulin-treated group as compared with the sulfonylurea group with the proviso that the insulin-treated group had preserved insulin secretory capacity and a high titer of GAD autoantibodies at the start of the study (61). An alternative interpretation of this study is that sulfonylureas are disadvantageous, in support of which sulfonylureas could theoretically promote apoptosis, apoptosis being one mechanism whereby insulin-secreting cells could be destroyed in autoimmune diabetes.
A pilot phase 2 trial in LADA patients (65) found that a tolerance induction plan using alum-formulated whole GAD (Diamyd) had a significant effect on the C-peptide response to a mixed meal consistent with modulation of the aggressive process. Another phase 2 trial in LADA patients using the peptide analog of heat shock protein 60 (Diapep 277) has been completed after initial positive results in protecting residual β-cell function in adult-onset type 1 diabetes patients (66) and in experimental models of the disease (67). These immunomodulatory studies, although small and preliminary, pioneer a novel approach toward the maintenance of islet cell function, itself a new field in the management of autoimmune diabetes.
In conclusion, LADA, whether viewed genetically, immunologically, metabolically, or clinically, occupies one end of a rainbow of features associated with autoimmune diabetes. The management and prevention of LADA need to be investigated to define the best strategy for treating this most prevalent form of autoimmune diabetes.
Acknowledgments
We thank all our collaborators, in particular Drs. Mohammed Hawa, Huriya Beyan, Chiara Guglielmi, Marta Vadacca, Sinead Brophy, and Mark Airey, for their contribution to the work in our laboratories and in the field.
The work in London, Swansea, and Rome was supported by grants from the Juvenile Diabetes Research Foundation, Develogen, Diabetes UK, Diabetes Twin Research Trust, and the European Union.
The authors have nothing to declare.
Abbreviations:
- GAD,
- HLA,
- IA,
- IAA,
- ICA,
- LADA,
Latent Autoimmune Diabetes In Adults Pdf 2017
. F E A T U R E R e v i e w
Latent Autoimmune Diabetes in Adults Ramachandra G. Naik, Barbara M. Brooks-Worrell, and Jerry P. Palmer Charles River Clinical Services Northwest (R.G.N.), Tacoma, Washington 98418; and Department of Medicine (B.M.B.-W., J.P.P.), Division of Endocrinology, Metabolism, and Nutrition, Department of Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, Washington 98108
Context: Autoantibodies that are reactive to islet antigens are present at the time of diagnosis in most patients with type 1 diabetes. Additionally, approximately 10% of phenotypic type 2 diabetic patients are positive for at least one of the islet autoantibodies, and this group is often referred to as “latent autoimmune diabetes in adults (LADA).” These patients share many genetic and immunological similarities with type 1 diabetes, suggesting that LADA, like type 1 diabetes, is an autoimmune disease. However, there are differences in autoantibody clustering, T cell reactivity, and genetic susceptibility and protection between type 1 diabetes and LADA, implying important differences in the underlying disease processes. Evidence Acquisition and Synthesis: In this clinical review, we will summarize the current understanding of LADA based on the MEDLINE search of all peer-reviewed publications (original articles and reviews) on this topic between 1974 and 2009. Conclusions: In LADA, diabetes occurs earlier in the -cell-destructive process because of the greater insulin resistance. Complexities arise also because of variable definitions of LADA and type 1 diabetes in adults. As immunomodulatory therapies that slow or halt the type 1 diabetes disease process are discovered, testing these therapies in LADA will be essential. (J Clin Endocrinol Metab 94: 4635–4644, 2009)
I
n clinical practice, the diagnosis of type 1 and type 2 diabetes is made using phenotypic characteristics such as age at onset, abruptness of onset of hyperglycemia, ketosis-proneness, degree of obesity (specifically central and intraabdominal), prevalence of other autoimmune diseases, and need for insulin replacement therapy. However, this clinical distinction is not always perfect (1, 2). The presence of genetic (3), immunological (4), and functional complexities (5) limits our ability to distinguish the type 1 vs. the type 2 disease processes. The disease process in classic type 1 patients is believed to be autoimmune in nature, whereas the disease process in classic type 2 is not autoimmune (6 – 8). However, there is increasing clinical evidence that highlights significant overlap between type 1 and type 2 diabetes, and the classification of diabetes into two main types has been challenged. Discovery of islet cell antibodies in 1974 in the sera of subjects with type 1 diabetes provided very strong evi-
dence that the -cell lesion of type 1 diabetes was autoimmune in nature (9, 10); autoimmune -cell dysfunction and destruction leads to insulin deficiency and generation of autoantibodies in the circulation, such as autoantibodies to islet-cell cytoplasm (ICA), and/or to glutamic acid decarboxylase 65 (GAD65; anti-GAD), and/or to the intracytoplasmatic domain of the tyrosine phosphatase-like protein IA-2 (IA-2A). Because there are no reliable markers for type 2 diabetes, absence of markers and/or manifestations of type 1 diabetes is often taken as indicating type 2 diabetes. It was demonstrated by Irvine et al. (11) that about 11% of subjects with type 2 diabetes were also positive for ICAs. Compared with ICA-negative (ICA⫺) type 2 diabetes, this ICA-positive (ICA⫹) subset of type 2 diabetes subjects tended to fail sulfonylurea therapy and needed insulin treatment earlier (11). Similar subsets of phenotypic type 2 diabetes subjects who are positive for the antibodies
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2009 by The Endocrine Society doi: 10.1210/jc.2009-1120 Received June 11, 2009. Accepted September 9, 2009. First Published Online October 16, 2009
Abbreviations: BMI, Body mass index; GAD, glutamic acid decarboxylase; HLA, histocompatibility leukocyte antigen; IAA, insulin autoantibodies; ICA, islet-cell cytoplasm; LADA, latent autoimmune diabetes of adults; ZnT8, zinc transporter.
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commonly found in type 1 diabetes have been demonstrated by several investigators. Zimmet (12) introduced the term “latent autoimmune diabetes of adults” (LADA) to describe this subgroup of adult phenotypic type 2 diabetes patients positive for an autoantibody to GAD (which implies the presence of autoimmunity and immune-mediated -cell dysfunction and damage as part of their disease process) and who present clinically without ketoacidosis and weight loss. As expected for an immune attack on the -cells, these patients also became insulin dependent more rapidly than “classic” type 2 diabetes patients who were negative for islet autoantibodies (12). Autoantibody-positive phenotypic type 2 diabetes patients or LADA have also been labeled as slowly progressive type 1 diabetes (13, 14), latent type 1 diabetes (15, 16), double diabetes (17), and type 1.5 diabetes (16, 18 –20).
autoantibodies characteristic of type 1 diabetes (27–29). These patients do not have a specific name like LADA, but defining LADA by the age criteria of older than 30 yr may be arbitrary and incorrect. Recently, it has been observed that the LADA patients share genetic features with both type 1 and type 2 diabetes (17). The role of obesity and the degree of insulin resistance in LADA are other areas of controversy. Normal -cells compensate for insulin resistance by secreting more insulin, and the product of insulin sensitivity and insulin secretion (“disposition index”) is normally a constant (30). Patients with insulin resistance will demonstrate hyperglycemia with a lesser degree of absolute insulin deficiency compared with subjects who are insulin-sensitive. Because LADA subjects span the spectrum from lean to obese, differences in insulin sensitivity could be an important variable in their physiology.
Definition, Demographic, and Clinical Characteristics
Humoral Immune Response
Epidemiological studies suggest that LADA may account for 2–12% of all cases of diabetes (12, 14, 18, 21–24). The typical LADA patient is generally older than 35 yr and nonobese, and diabetes is controlled initially with diet; however, within a short period (months to years), dietary control fails, requiring oral agents and progression to insulin dependency. The progression to insulin dependence in LADA patients is believed to be more rapid than in antibody-negative, obese type 2 diabetes subjects. The eventual clinical features of these patients include weight loss, ketosis proneness, unstable blood glucose levels, and an extremely diminished C-peptide reserve (14). We do not know whether autoimmune diabetes in adults is due to the same underlying disease process as childhood type 1 diabetes (16), and phenotypically one can see at least three separate populations of autoimmune diabetes in adults: LADA, adult onset type 1 diabetes, and obese patients with phenotypic type 2 diabetes who are antibody positive (type 1.5) (16). In an attempt to standardize the definition of LADA, the Immunology of Diabetes Society has recently proposed the following criteria: patients should be at least 30 yr of age, positive for at least one of the four antibodies commonly found in type 1 diabetic patients (ICAs and autoantibodies to GAD65, IA-2, and insulin), and not treated with insulin within the first 6 months after diagnosis. Although the latter requirement is subjective, it is meant to distinguish LADA and type 1 diabetes occurring in patients more than 30 yr of age (25, 26). However, similar pathophysiology also occurs in obese children who are non-ketosis-prone but who have
Antibody positivity and clustering The presence of autoantibodies along with islet-reactive T cells in both LADA and classic childhood type 1 diabetes provides strong evidence that the underlying disease process in both patient groups is autoimmune. However, there are differences in antibodies between LADA and type 1 diabetes. All four well-described type 1 diabetes-associated islet autoantibodies—ICAs, anti-GAD, IA2A, and insulin autoantibodies (IAA)—and the more recently identified zinc transporter (ZnT8) antibody are common in childhood type 1 diabetes; many type 1 diabetes patients are also positive for multiple autoantibodies (31). Thus, antibody clustering is a characteristic feature of classic childhood type 1 diabetes. Many researchers have demonstrated that anti-GAD and ICA are much more common than IAA, IA-2A, and ZnT8 antibodies in LADA patients vs. type 1 patients (17, 18, 31–34). Wenzlau et al. (31) reported that ZnT8 autoantibodies were detected in up to 80% of new-onset type 1 diabetes subjects compared with less than 2% of controls, less than 3% of type 2 diabetes patients, and up to 20% of patients with other autoimmune diseases. By definition, the presence or absence of autoantibodies distinguishes between patients with “classic” nonautoimmune type 2 diabetes and LADA (25). In our study of 125 adult phenotypic type 2 patients screened for autoantibodies, 36 (28.8%) patients were positive for at least one autoantibody (Fig. 1) (18). In nondiabetic relatives of patients with type 1 diabetes, risk of future type 1 diabetes is directly proportional to the number of positive autoantibodies (35–37). Positivity for only one autoantibody (ICA or anti-GAD) is characteristic
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5.6%
IAA
ICA
GAD 38.9%
5.6%
27.8% 27.8% 16.7%
IA-2
5.6%
FIG. 1. Clustering of autoantibodies in autoantibody-positive patients. Numbers (%) refer to the percentage of the antibodypositive patients who were positive for the respective antibodies. [Reproduced with permission from R. Juneja et al.: Metabolism 50: 1008 –1013, 2001 (18).]
of LADA patients (18, 20, 33, 38 – 41). Recent studies have reported that the clinical characteristics of LADA patients correlate with the titer and numbers of diabetesassociated autoantibodies (42– 44). Simultaneous presence of multiple autoantibodies and/or a high titer of antiGAD autoantibodies, compared with single and low-titer autoantibody, was associated with an earlier age at onset, lower fasting C-peptide values, and a higher likelihood for future insulin requirement (44, 45). Antigenic differences between LADA and type 1 diabetes GAD and IA-2 could block ICA staining in approximately 60% of sera from type 1 diabetes subjects but only in 37.5% of sera from people with LADA, suggesting that autoantibodies to antigens other than GAD and IA-2 are more prevalent in LADA (46). The IgG4 subclass of antiGAD has been demonstrated to be more frequent in LADA than in type 1 diabetes, implying a more “regulated” immune response (a dominant TH2 immune response) in LADA (47). We identified possible differences in epitope specificity of anti-GAD in LADA vs. type 1 diabetes using recombinant 35S-GAD65/67 fusion proteins (48). More than 90% of type 1 diabetes patients’ sera bound to the middle or COOH-terminal portion of GAD65; similar binding was seen in only 65% of sera from LADA patients. In contrast, the NH2-terminal portion of GAD65 was recognized by 20% of LADA patients compared with 5% of type 1 diabetic patients (48). Similar results using GAD65specific recombinant Fabs have also been found in our recent studies (49). The United Kingdom Prospective Diabetes Study (UKPDS) has shown that although GAD autoantibodies persisted for 5 yr after diagnosis of LADA, some GAD autoantibodies are reactive to different GAD65
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epitopes compared with type 1 diabetes and are not associated with disease progression or future insulin requirements (50). A recent Italian study has demonstrated that autoantibody reactivity to IA-2 in LADA patients may well be much more frequent than so far reported if a particular IA-2 (256-760) construct is used, and this can be considered as a new, sensitive, and novel diagnostic tool for the detection of islet autoimmunity in subjects with type 2 diabetes (51).
T Cell Studies T cell responses to islet proteins in type 1 diabetes and LADA T cell assays to measure reactivity to islet antigens in human type 1 diabetes have been developed over the last several years; one such assay, called cellular immunoblotting assay and developed by our group, uses proteins from human islets separated into 18 different molecular weight regions using SDS-PAGE. Excellent sensitivity and specificity for differentiating type 1 diabetes from controls was demonstrated by this assay in a masked National Institutes of Health—Immune Tolerance Network Workshop (52). Similar results were demonstrated in a subsequent masked TrialNet workshop (53). T cells responding to multiple islet proteins have been found in LADA patients with and without autoantibodies (38, 39, 54, 55), in type 1 diabetes patients (56 – 61), and in subjects at risk of developing type 1 diabetes before development of clinical disease (57). Using the cellular immunoblotting assay, we have identified differences in islet proteins recognized by T cells from type 1 vs. LADA (54). As illustrated in Fig. 2, there are some islet proteins that T cells from both type 1 diabetes and LADA subjects appear to respond to equally (molecular mass, 116, 97, and 60 kDa). However, there are also molecular mass regions that may differentiate T cell responses from type 1 diabetes vs. LADA (proteins in the molecular mass regions 65–90 and 21–38 kDa). It is not yet understood which immunological mechanisms are important in the delay and apparent differences in the pathogenesis of LADA vs. type 1 diabetes. Many of the above findings point to potential differences in immunological regulatory mechanisms. T cell responses to islets in type 2 diabetes and LADA We have recently identified a group of phenotypic type 2 diabetes subjects who have T cells reactive to islet proteins but are negative for islet autoantibodies (55). We have termed this group of patients as T-LADA. Thus, as-
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Type 1 Ab (+) Type 2
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66). LADA subjects appear to have a faster decline in Cpeptide levels compared with people with autoantibody negative type 2 diabetes (33, 43, 66). In comparison, a greater rate of decline in C-peptide has been reported in adult type 1 diabetes compared with LADA (33, 67). Other investigators have also observed differences in insulin secretion between type 1 diabetes, LADA, and type 2 diabetes. Gottsater et al. (67) found that the level of insulin secretion in LADA was intermediate between type 1 and type 2 diabetes and that fasting and stimulated Cpeptide were reduced in LADA compared with type 2 diabetes.
* p<0.05
FIG. 2. T cell responses of 12 type 1 diabetes patients (closed circles) and 11 autoantibody-positive type 2 patients (type 1.5 patients; open squares). The percentage of subjects responding to each molecular mass region is shown. A positive response is taken as SI ⬎2.0. Blot sections correspond to molecular mass regions ⬎200 kDa (1) and ⬍14 kDa (18). *, P ⬍ 0.05 indicates significant difference. [Reproduced with permission from B. M. Brooks-Worrell et al.: Diabetes 48:983–988, 1999 (54).]
sessing patients for T cell responses to islet proteins may help distinguish LADA from type 2 diabetes, especially if the LADA subjects are autoantibody negative. With the identification of T-LADA, the use of only autoantibodies to screen phenotypic type 2 diabetes subjects for autoimmune diabetes may need to be reevaluated (55). Recently, we observed the importance of assessing T cell responses from type 2 diabetes subjects to islet proteins by demonstrating that identifying subjects with type 2 diabetes with T cells responsive to islet proteins identified those with a more severe -cell lesion compared with assessing islet autoantibodies alone (62). Other T cell studies In health, immunological tolerance is maintained by multiple central and peripheral mechanisms including the action of a specialized set of regulatory T cells characterized by expression of CD4 and CD25 (CD4⫹CD25⫹FOXP3⫹ Treg). It has been suggested that a defect in this cell population, either numerically or functionally, could contribute to the development of autoimmune diseases, such as type 1 diabetes (63). Yang et al. (64) in their study of lymphocyte subsets showed that CD4⫹ regulatory T cells are reduced and the expression of FOXP3 mRNA in CD4⫹ T cell was decreased in LADA patients.
Islet -Cell Function, Insulin Resistance, and Islet Inflammation -Cell function -cell dysfunction in LADA has been reported to be intermediate between type 1 and type 2 diabetes (43, 65,
Insulin resistance The role of insulin resistance and its contribution to the pathophysiology of LADA is controversial; the degree of insulin resistance in LADA has been reported to be less than in type 2 diabetes and comparable to type 1 diabetes (68, 69). We have recently compared insulin resistance using the homeostasis model in LADA, antibody-negative type 2 diabetes, and normal control subjects correcting for the effect of body mass index (BMI) (26, 70). There was a positive correlation of BMI with insulin resistance in both LADA and type 2 diabetes, and insulin resistance was remarkably similar in both groups when corrected for BMI (70). Furthermore, subjects with both LADA and type 2 diabetes were more insulin resistant than normal control subjects when corrected for BMI. Some studies have reported a significantly lower mean BMI in LADA compared with patients with type 2 diabetes (69, 71), whereas other studies do not show a difference (70). However, the range of BMIs is often large, with tremendous overlaps between LADA and type 2 diabetes (18). A recent study in adult European diabetes patients has shown that the prevalence of metabolic syndrome is significantly higher in type 2 diabetic patients than in patients with LADA or adults with type 1 diabetes (72); it was further shown that metabolic syndrome is not more prevalent in patients with autoimmune diabetes than in control subjects, and metabolic syndrome is not a characteristic of autoimmune diabetes (72). Islet inflammation in type 1 and 2 diabetes It is also becoming increasingly evident that many factors that are involved in the type 1 diabetes-specific process are also integral to the -cell lesion in type 2 diabetes, including IL-1, Fas, nuclear factor-B, and increased expression of c-Myc (73, 74). Moreover, recent studies have also shown macrophage infiltration in islets of type 2 diabetes subjects (73, 74). The mechanisms leading to cytokine-induced -cell dysfunction in type 1 diabetes and to nutrient-induced -cell dysfunction in type 2 diabetes may
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share common final pathways, including IL-1 signaling (73, 74). Thus, there seems to be a wide spectrum of associations between inflammatory reactions and the various diabetic syndromes. Type 1 diabetes is at one end of the spectrum for which there is convincing evidence that a chronic inflammation of the islets is an important feature of disease pathogenesis; at the opposite end of the spectrum is type 2 diabetes, which is clearly associated with systemic inflammation that could be either the cause or the consequence of some of the main features of the disease (75). Thus, one may hypothesize that classic type 1 and type 2 diabetes reflect two extremes of a continuum, connected by the central role of the failing -cell (73). Finally, somewhere between these two extremes, one finds LADA, which seems to share some features of both extremes (75).
Genetic Susceptibility and Protection Studies from both of the animal models (the NOD mouse and the BB rat) and human type 1 diabetes confirm the presence of strong genetic control over both susceptibility to and protection from diabetes. The greatest risk and protection is conferred by the major histocompatibility complex region, histocompatibility leukocyte antigen (HLA) in humans; however, other genes are also involved in the process. HLA associations It is well established that HLA DR3, DR4, and DQ1*0201 and 0302 confer increased risk of type 1 diabetes. It is also known that other HLA alleles including DR2 and DQ1*0301 and 0602 confer protection against type 1 diabetes. An increased frequency of HLA susceptibility alleles has been observed in LADA patients (20, 33, 34, 76, 77), but whether or not there are subtle differences between type 1 diabetes and LADA for specific alleles is controversial (20, 77, 78). The most consistent HLArelated finding is a relatively high frequency, compared with type 1 diabetes, of the protective alleles DR2 and DQ1*0602 in subjects with LADA (79). The protection associated with DR2/DQ1*0602 may partially explain the age of onset of LADA vs. childhood type 1 diabetes. A recent study compared a group of LADA subjects with control and adult type 1 diabetes (33). It was found that the HLA high-risk haplotype DR4-DQ1*0302 and the DR3/DR4-DQ1*0302 genotype were significantly more common in subjects with LADA compared with control subjects, whereas the frequencies were no different in LADA vs. adult onset type 1 diabetes (33). One could, thus, possibly hypothesize that the type 1 diabetes disease process is more aggressive, resulting in clinical presenta-
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tion at a younger age in individuals with more susceptibility genes and less protective genes, and vice versa. Non-HLA associations Allelic variations at several non-HLA loci with increased risk for and protection from classic type 1 diabetes have also been investigated in subjects with LADA. An increased frequency of the cytotoxic T lymphocyte antigen-4 genotype A/G is seen in both type 1 diabetes and LADA, suggesting a similar role in both these types of diabetes (80). Similarly, allelic variation in the variable number of tandem repeats of the 5⬘ region of the insulin gene has been reported in both type 1 diabetes and LADA, but the relative risk associated with the 1S/S genotype was reported to be significantly stronger for LADA than for type 1 diabetes (81). Microsatellite polymorphism in the major histocompatibility complex class I chain-related gene A (MICA) has been associated with different autoimmune diseases including type 1 diabetes. MICA5 is associated with type 1 diabetes under the age of 25 yr, whereas MICA5.1 is associated with both LADA and type 1 diabetes over 25 yr of age (78, 82). Other associations reported include an allelic polymorphism within the promoter region of the TNF-␣ gene and a significantly lower frequency of TNF2 allele in LADA compared with type 1 diabetes or nondiabetic control subjects (83). Recent genome-wide association studies demonstrated a link between the ZnT8 gene polymorphisms and type 2 diabetes, although ZnT8 autoantibodies are rarely detected (84 –90). More recently, a single polymorphic Arg325 encoding residue polymorphism in SLC30A8 has been shown to be associated with type 1 diabetes risk (91). Common variants in the TCF7L2 gene, in association with HLA-DQ1 genotyping, can distinguish anti-GAD positive and antiGAD negative diabetes subjects diagnosed between the ages of 15 and 34 yr (92). But, the TCF7L2 gene variants do not distinguish between autoimmune and nonautoimmune diabetes diagnosed between the ages of 40 and 59 yr, suggesting that the disease pathogenesis in middle-aged (40 –59 yr) anti-GAD-positive subjects is different from young (15–34 yr) anti-GAD-positive diabetes subjects (92). Also, subjects with LADA share the same TCF7L2 genotype with type 2 diabetes (17). Thus, subjects with LADA appear to share genetic determinants common to both type 1 and 2 diabetes. Significance of family history Family history of diabetes has been identified as a risk factor for the development of diabetes, both type 1 and type 2 (25). Familial clustering of diabetes is believed in part to be due to a combination of shared genetic and environmental factors. For both type 1 and type 2 diabe-
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tes, the risk of developing diabetes increases with an increasing number of affected relatives (92–94). Interesting recent reports have shown familial clustering of type 1 and type 2 diabetes genes and have suggested that selected susceptibility gene variants may be involved in the pathogenesis of type 1 and type 2 diabetes (73). The results of the Nord-Trøndelag Health Study (95) showed that family history of diabetes, although the type of diabetes in the relatives was unknown, was also a strong risk factor for the development of LADA.
in part be attributed to the ability of rosiglitazone to suppress or decrease the autoimmune T cell-mediated destruction of the -cells. Other antidiabetic agents that have emerged as putative protectors of -cells include glucagon-like peptide-1 analogs and IL-1 receptor antagonist (108). Further testing is needed to determine the best initial and long-term treatment of autoimmune phenotypic type 2 diabetes. Another potential treatment for diabetes is antigen-specific immunomodulation. A randomized, double-blind, placebo-controlled dose-finding phase IIa GAD vaccine study in LADA subjects demonstrated not only safety of the drug product, Diamyd, but also efficacy in preserving -cell function in LADA (109). Subsequently, the same dose of GAD administered twice 28 d apart preserved C-peptide in classic childhood type 1 diabetes (110). A recently published 5-yr follow-up study of the 47 LADA patients who were given GAD-alum at escalating dosages showed that the treatment was safe and did not compromise -cell function (111). The increase in fasting and stimulated C-peptide levels that had previously been reported after 6 months in the group given 20 g was maintained during the 5 yr follow-up (111). Because of the possible differences in the immune system’s recognition of -cell antigens between LADA and type 1 diabetes, different islet antigens might be more important for modulating the autoimmune attack against the -cells in type 1 diabetes compared with LADA. Thus, the success of antigen-based therapies may depend upon whether or not tolerance to the islet antigens is reinstated by the therapy. We have hypothesized that antigen spreading is more restricted in autoimmune diabetes in adults than in childhood type 1 diabetes (16, 54) and that some antigens may be more important in the type 1 diabetes vs. LADA disease process and possibly vice versa. Treatment with some antigens might be efficacious in both autoimmune diabetes in adults and childhood type 1 diabetes, such as the GAD treatment mentioned above, whereas other antigens might be selectively effective in childhood type 1 diabetes or LADA. Because the prevalence of type 2 diabetes is high and is increasing rapidly, even if only 10% are LADA subjects, this is a population of patients two or three times larger than the classical childhood type 1 diabetes patient population, and thus the efficacy of specific treatment options, including insulin, thiazolidinediones, and immunomodulatory regimens, is very important.
Therapeutic Interventions Knowing whether or not the mechanisms of the immunological damage to and destruction of the pancreatic -cells is the same in all patients with autoimmune diabetes has important implications from a therapeutic viewpoint. Immunomodulatory therapies (such as anti-CD3), have been found to be efficacious in modulating the type 1 diabetes disease process (96). Because LADA is more common than classic childhood type 1 diabetes, it will be interesting to determine whether these treatments are similarly effective in LADA. Previous studies in the NOD mouse, the BB rat, and in a human pilot trial had shown that parenteral insulin therapy protects against type 1 diabetes (97, 98). Two studies from Japan demonstrated better preservation of -cell function with insulin compared with sulfonylurea in ICApositive and anti-GAD-positive phenotypic type 2 diabetes subjects (99, 100). Additional studies are needed to determine whether the beneficial effects of insulin treatment in Japanese LADA patients (99, 100) can be extended to all patients with LADA. Speculations have been presented regarding the value of thiazolidinediones in the treatment of LADA, not only because of their ability to improve insulin sensitivity, but also because of their antiinflammatory effect. Rosiglitazone has been reported to increase IL-4 and IL-10 levels and decrease nuclear factor-〉-binding activity in mononuclear cells, monocyte chemoattractant protein-1, soluble intercellular adhesion molecule-1, interferon-␥, IL-12, IL-18, TNF-␣, and C-reactive proteins (101–106). If the decline in -cell function in type 2 diabetes patients is in part a result of T cell-mediated autoimmune destruction of the -cells, then the addition of an antiinflammatory medication, such as rosiglitazone, might slow the decline in -cell function. In fact, rosiglitazone was recently reported to provide greater preservation of islet -cell function in islet autoimmune LADA subjects (GADA⫹) compared with a group of LADA subjects treated with insulin alone during a 3-yr follow-up (107). We hypothesize that the preservation of -cell function in this study and others may
Acknowledgments Address all correspondence and requests for reprints to: Jerry P. Palmer, M.D., Director of Endocrinology, Department of Veterans Affairs Puget Sound Health Care System, Professor of Medicine,
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University of Washington, 1660 South Columbian Way (111), Seattle Washington 98108. E-mail: [email protected] Disclosure Summary: All the authors have disclosed no conflict of interest pertinent to this publication.
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